Inability to work following COVID-19 vaccination among healthcare workers - an important aspect for future booster vaccinations

BackgroundCOVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections, especially among highly exposed healthcare workers (HCWs). However, vaccine-related inability to work among HCWs could overstrain healthcare systems. MethodsThis study examined sick leave and intake of pro re nata (PRN) medication after the first, second and third COVID-19 vaccination in HCWs. Subgroup analyses were performed for different vaccines, gender, healthcare professions, and for HCWs aged at least 30 years. Data was collected by using an electronic questionnaire. FindingsAmong 1,704 HCWs enrolled, in total 595 (34{middle dot}9%) HCWs were on sick leave following at least one COVID-19 vaccination, leading to a total number of 1,550 sick days. Both the absolute sick days and the rate of HCWs on sick leave significantly increased with each subsequent vaccination. Comparing BNT162b2mRNA and mRNA-1273 the difference in sick leave was not significant after the second dose, but mRNA-1273 induced a significantly longer and more frequent sick leave after the third. InterpretationA considerable number of HCWs have been on sick leave after COVID-19 vaccination, staff absences increase with each additional dose, depend on the vaccine, and vary between HCWs gender, and profession. In the light of further COVID-19 infection waves and booster vaccinations, there is a risk of additional staff shortages due to post-vaccination inability to work, which could acutely overload healthcare systems and jeopardise patient care. These findings will aid further vaccination campaigns to minimise the impact of staff absences on the healthcare system. FundingThis study was funded by the Federal Ministry for Education and Science (BMBF) via a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD.

Clinical accuracy of SARS-CoV-2 rapid antigen testing in screening children and adolescents in comparison to RT-qPCR, November 2020 to September 2022

BackgroundRapid antigen detection tests (RDT) are an easily accessible, feasible, inexpensive, and point-of-care method in SARS-CoV-2 diagnostics - established in adults as well as in children and adolescents. Despite this, large-scale data of clinical performance in the paediatric population especially regarding the influence of SARS-CoV-2 virus variants of concern (VOC) and COVID-19 vaccination on test accuracy is rare. MethodsThis single-centre prospective diagnostic study evaluates three RDT (NADAL(R), Panbio, MEDsan(R)) in comparison to quantitative reverse transcription polymerase chain reaction (RT-qPCR). 9,760 oropharyngeal screening samples regarding SARS-CoV-2 VOC and COVID-19 vaccination in paediatric hospitalised patients aged younger than 18 years were enrolled. FindingsRDT sensitivity was 44{middle dot}7% (157/351, 95% CI 39{middle dot}6%-50{middle dot}0%) compared to the reference standard RT-qPCR, specificity 99{middle dot}8% (9,392/9,409, 95% CI 99{middle dot}7%-99{middle dot}9%). Most SARS-CoV-2 infections considered were caused by Omicron VOC. Diagnostic accuracy of RDT depended on specimen containing viral load with a decreasing RDT sensitivity by descending viral load, corresponding with a significantly impaired sensitivity in asymptomatic children. A sensitivity of 71{middle dot}0% was obtained for a viral load higher than 106 SARS-CoV-2 RNA copies per ml suggested as infectivity threshold. No significant differences in RDT sensitivity could be observed regarding gender, symptoms, COVID-19 vaccination status, and VOC. InterpretationIn a paediatric population, RDT have proven to reliably detect potentially highly infectious patients with a viral load of at least 106 SARS-CoV-2 RNA copies per ml. Due to the low sensitivity in asymptomatic individuals, the usefulness of RDT seems limited in large-scale SARS-CoV-2 screening programs. FundingFederal Ministry for Education and Science (BMBF), Free State of Bavaria

Bivalent BNT162b2mRNA original/Omicron BA.4-5 booster vaccination: adverse reactions and inability to work compared to the monovalent COVID-19 booster

In the light of emerging SARS-CoV-2 variants of concern (VOC), bivalent COVID-19 vaccines combining the wild-type spike mRNA with an Omicron VOC BA.1 or BA.4-5 spike mRNA became available. This non-randomized controlled study examined adverse reactions, PRN (pro re nata) medication intake and inability to work after a fourth COVID-19 vaccination among 76 healthcare workers. As fourth dose either the original, monovalent BNT162b2mRNA (48.7%) or the bivalent BNT162b2mRNA original/Omicron BA.4-5 vaccine (51.3%) was administered. The rate of adverse reactions for the second booster dose was significantly higher among participants receiving the bivalent 84.6% (95% CI 70.3%-92.8%; 33/39) compared to the monovalent 51.4% (95% CI 35.9-66.6%; 19/37) vaccine (p=0.0028). Also, there was a trend towards an increased rate of inability to work and intake of PRN medication following bivalent vaccination. In view of preprints reporting inconclusive results in neutralizing antibody levels between the compared vaccines, our results and further studies on safety and reactogenicity of bivalent COVID-19 booster vaccines are highly important to aid clinical decision making in the choice between bivalent and monovalent vaccinations.

Immunogenicity and safety of coadministration of COVID-19 and influenza vaccination among healthcare workers

BackgroundA third dose of COVID-19 vaccination ( COVID booster vaccination) has become established as an important measure to strengthen the immune response against SARS-CoV-2. In contrast, seasonal influenza vaccination has been an important infection prevention measure for years, especially among highly exposed healthcare workers (HCWs). Coadministration of vaccines against COVID-19 and seasonal influenza could be an efficient strategy to protect HCWs from two major viral respiratory infections. Yet, the immunogenicity and safety of coadministration remains to be evaluated. MethodsThis study examines the differences in Anti-SARS-CoV-2-Spike IgG antibody formation as well as side effects based on a digital questionnaire after a third COVID-19 vaccination with or without coadministration of a seasonal quadrivalent influenza vaccine (Influvac Tetra vaccine 2021/2022). 1,231 HCWs were recruited who received a mRNA-based booster COVID-19 vaccination (mRNA-1273 or BNT162b2mRNA) after basic immunisation with BNT162b2mRNA twice. Anti-SARS-CoV-2-Spike IgG levels were determined at least 14 days after vaccination by SERION ELISA agile SARS-CoV-2 IgG. FindingsAnti-SARS-CoV-2-Spike IgG concentrations were by 25{middle dot}4% lower in individuals with coadministration of the seasonal quadrivalent influenza vaccination than without (p<0{middle dot}01). There was no statistically significant difference in the reported side effects. The concentration of Anti-SARS-CoV-2-Spike IgG was higher in HCWs who had received the influenza vaccine concomitantly with mRNA-1273 than with BNT162b2mRNA as third COVID-19 vaccine (p<0{middle dot}0001). InterpretationCoadministration of the seasonal quadrivalent influenza vaccine significantly limits the levels in Anti-SARS-CoV-2-Spike IgG levels, with a more restricted elevation in case of a BNT162b2mRNA booster vaccination compared with mRNA-1273 vaccine. The reduced humoral immune response in case of coadministration needs to be considered in seasonal vaccination recommendations, although the consequences of lower Anti-SARS-CoV-2-Spike IgG levels for the protection against SARS-CoV-2 infection and severe COVID-19 disease course are currently unknown. An augmented mRNA-based COVID-19 vaccine dosage may compensate for the restricted immunogenicity in case of coadministration. FundingThis study was funded by the Federal Ministry for Education and Science (BMBF) through a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSFor evaluation of the previously published evidence, PubMed and medRxiv were searched for the terms "influenza vaccination", "influenza vaccine", "influenza", "flu", "seasonality", combined with "coadministration", "concomitant", "COVID-19 vaccination", "COVID-19 vaccine", "SARS-CoV-2", in title or abstract, published between 1st of January 2020 and 18th of May 2022. To date, it is unclear if coadministration of COVID-19 and influenza vaccine is effective and safe, particularly in the cohort of healthcare workers (HCWs) as key public health stakeholders. For the subunit COVID-19 vaccine NVX-CoV2373, an impairment of Anti-SARS-CoV-2-Spike IgG levels has been shown in individuals coadministered with a seasonal influenza vaccine. The two previously published studies on coadministration of a mRNA-based COVID-19 and a seasonal quadrivalent influenza vaccine have reported a restriction of humoral Anti-SARS-CoV-2-Spike immune response in the coadministration group. These examinations were conducted with limited correspondence to real-life conditions and in smaller cohorts. Additionally, these former studies do not consider the important aspect of side effects as a possible direct effect of the prevention measure on the availability of public health care in combination with Anti-SARS-CoV-2-Spike IgG levels. In summary, the humoral immunogenicity and side effects of a coadministered third COVID-19 and a seasonal influenza vaccine are still unclear and the limited available data is not transferable to the general public. Added value of this studyWe performed the first large-scale real-life evaluation of humoral immunogenicity and side effects of COVID-19 and influenza vaccine coadministration in HCWs. Anti-SARS-CoV-2-Spike IgG levels were significantly lower in the coadministered cohort compared to the not coadministered control group, stratified by third COVID-19 vaccine (BNT162b2mRNA or mRNA-1273). Anti-SARS-CoV-2-Spike IgG post-vaccine elevation was lower among BNT162b2mRNA vaccinated HCWs than in those vaccinated with mRNA-1273 as a third COVID-19 vaccination. The influence of the seasonal quadrivalent influenza vaccine is evaluated in a cohort including 1,231 HCWs in total, covering a broad age range. Coadministration did not lead to an increase in side effects, which is a central requirement for considering the option of coadministration, given the role of HCWs as key personnel in maintaining health care capacities. Implications of all the available evidenceOur data suggest, that coadministration of third mRNA-based COVID-19 and quadrivalent seasonal influenza vaccine is safe and immunogenic, although it leads to a slightly reduced Anti-SARS-CoV-2-Spike antibody formation. While the clinical impact of the observed reduction in humoral Anti-SARS-CoV-2-Spike immune response for protection against SARS-CoV-2 infection and severe COVID-19 disease is still unclear, influenza vaccination remains an important infection prevention measure, especially among highly exposed HCWs. The coadministration does not increase side effects but may improve vaccination rate. A higher-dosed mRNA-based COVID-19 vaccine may compensate for the restricted immunogenicity in case of seasonal influenza vaccine coadministration. Our results will support the development of public health recommendations for coadministration of COVID-19 and influence vaccines in anticipation of the imminent infection waves in the coming winter season.

Influencing factors of Anti-SARS-CoV-2-Spike IgG antibody titres in healthcare workers - A cross-section study

BackgroundAgainst the background of the current COVID-19 infection dynamics with the rapid spread of SARS-CoV-2 variants of concern (VOC), above all the Omicron VOC, the immunity of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. Vaccination plays a central role in reducing the severity and potentially the spread of the disease. In healthcare, this is important to prevent disease-related staff shortages. However, there is a lack of data on factors influencing the humoral immune response. AimThe aim of our study was to determine factors influencing the level of Anti-SARS-CoV-2-Spike IgG after SARS-CoV-2 infection or vaccination in healthcare workers. Methods1,750 study participants were recruited who met the following inclusion criteria: age [≥] 18 years, PCR-confirmed SARS-CoV-2 infection and/or at least one dose of COVID-19 vaccination, working in health care. Anti-SARS-CoV-2-Spike IgG titres were determined by SERION ELISA agile SARS-CoV-2 IgG. ResultsMean Anti-SARS-CoV-2-Spike IgG levels increased significantly with the number of COVID-19 vaccinations (92.2 BAU/ml for single dose, 140.9 BAU/ml for two doses and 1,144.3 BAU/ml after threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titres compared with participants after infection only (525.4 BAU/ml vs. 105.7 BAU/ml). Anti-SARS-CoV-2-Spike IgG titres declined significantly with time after administration of the second vaccine dose. Smoking and high age were associated with lower titres. ConclusionBoth recovered and vaccinated HCWs presented a predominantly good humoral immune response with decreasing antibody levels over the temporal course. Smoking and higher age limited the humoral SARS-CoV-2 immunity. This reduced immune response is an important aspect as people with these risk factors are recognized as people with an increased risk for a severe course of disease.

Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCR

BackgroundAntigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data is sparse. MethodsIn a prospective performance evaluation study, RDT from three manufacturers (NADAL(R), Panbio, MEDsan(R)) were compared to quantitative reverse transcription polymerase chain reaction (RT-qPCR) in 5 068 oropharyngeal swabs for detection of SARS-CoV-2 in a hospital setting. Viral load was derived from standardized RT-qPCR Cycle threshold (Ct) values. The data collection period ranged from November 12, 2020 to February 28, 2021. FindingsOverall, sensitivity of RDT compared to RT-qPCR was 42{middle dot}57% (95% CI 33{middle dot}38%-52{middle dot}31%), and specificity 99{middle dot}68% (95% CI 99{middle dot}48%-99{middle dot}80%). Sensitivity declined with decreasing viral load from 100% in samples with a deduced viral load of [≥]108 SARS-CoV-2 RNA copies per ml to 8{middle dot}82% in samples with a viral load lower than 104 SARS-CoV-2 RNA copies per ml. No significant differences in sensitivity or specificity could be observed between the three manufacturers, or between samples with and without spike protein variant B.1.1.7. The NPV in the study cohort was 98{middle dot}84%; the PPV in persons with typical COVID-19 symptoms was 97{middle dot}37%, and 28{middle dot}57% in persons without or with atypical symptoms. InterpretationRDT are a reliable method to diagnose SARS-CoV-2 infection in persons with high viral load. RDT are a valuable addition to RT-qPCR testing, as they reliably detect infectious persons with high viral loads before RT-qPCR results are available. FundingGerman Federal Ministry for Education and Science (BMBF), Free State of Bavaria Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMED an MedRxiv for articles including "COVID-19", "COVID", "SARS-CoV-2", "coronavirus" as well as "antigen detection", "rapid antigen test", "Point-of-Care test" in title or abstract, published between January 1, 2020 and February 28, 2021. The more than 150 RDT on the market at the end of February 2021 represent a huge expansion of diagnostic possibilities.1 Performance of currently available RDT is evaluated in several international studies, with heterogeneous results. Sensitivity values of RDT range from 0{middle dot}0%2 to 98{middle dot}3%3, specificity from 19{middle dot}4%4 to 100{middle dot}0%.2,5-14. Some of this data differs greatly from manufacturers data. However, these previously published performance evaluation studies were conducted under laboratory conditions using frozen swabs, or in small cohorts with middle-aged participants. Comparable RDT performance data from large-scale clinical usage is missing.5-19 Added value of this studyBased on previous examinations the real life opportunities and limitations of SARS-CoV-2 RDT as an instrument of hospital infection detection and control are still unclear as well as further study results are limited in transferability to general public. Our findings show that RDT performance in daily clinical routine is reliable in persons with high viral for punctual detection and isolation of infectious persons before RT-qPCR become available. In persons with lower viral load, or in case of asymptomatic patients SARS-CoV2 detection by RDT was unsuccessful. The general sensitivity of 42{middle dot}57% is too low to accept the RDT in clinical use as an alternative to RT-qPCR in diagnosis of COVID-19. Calculated specificity was 99.68%. The results are based on a huge study cohort with more than 5 000 participants including a representative ages structure with pediatric patients up to geriatric individuals, which portrays approximately the demographic structure of the local society. Implications of all the available evidenceDue to the low general sensitivity RDT in clinical use cannot be accepted as an alternative but as an addition to RT-qPCR in SARS-CoV-2 diagnosis. The benefit of early detection of highly infectious persons has to be seen in context of the effort of testing and isolation of false positive tested persons.